Dendritic cells (DCs) are heterogeneous APCs that are pivotal regulators of T cell immunity--they both prime T cells against pathogens and prevent autoimmune responses against self antigens. One DC subset, Langerhans cells (LCs), resides in the epidermis and has been proposed to be the primary DC subtype involved in presentation of cutaneous antigen to naive T cells. However, the specific contributions that LCs and other DC subsets make in initiation, effector phase and regulation of immune responses has not been deciphered due to the absence of a mice lacking specific dendritic cells subsets in the setting of an otherwise normal immune system. We hypothesize that LCs are unique in their ability to present cutaneous antigens and are functionally required for the initiation of contact hypersensitivity and the maintenance of peripheral tolerance to cutaneous antigens. To test this hypothesis we have undertaken the generation of mice with a selective absence or functional impairment of Langerhans cells. We have generated BAC transgenic mice that specifically express human Langerin in LCs. We plan to 1) generate new transgenic lines using the human Langerin promoter to express Diphtheria toxin to ablate LCs and Cre which will be bred to floxed I-Abeta mice to eliminate MHC-II expression in LCs; 2) test our hypothesis on the functional roles of LCs by examining contact hypersensitivity (CHS) and maintenance of peripheral tolerance in LC-deficient animals; and 3) extend our transgenic approach to target other DC subsets. My immediate career goal is to continue basic science investigation as a junior faculty member in the Department of Dermatology at the Yale School of Medicine. This proposed 5 year mentored program will allow me to develop a unique model system that will provide the basis for many long term projects and collaborations and further my development into an independent investigator.